The subject invention relates to a method for atopy prophylaxis, agents for use therein and methods for preparing and using same.
Atopy is generally understood to mean a familially occurring hypersensitivity to environmental substances of skin and mucosae, with an increased predisposition to develop immediate hypersensitivity to substances originating from the natural environment. It has been postulated that environmental substances induce the production of antibodies of class IgE (immunoglobulin E), which initiate further allergic reactions. Atopy is manifest at the loci of contact with the so-called "allergens" (environment-derived substances such as pollen, spores, domestic dust, etc.), for example
in the eyes as an allergic conjunctivitis; PA1 at the nasal mucosa as an allergic rhinitis (hay fever); PA1 in the lungs as an allergic bronchial asthma; PA1 on the skin as chronic or chronic-relapsing dermatitis (atopic dermatitis).
Atopy appears to be genetically-linked and afflicts about 10% of the population, with a recent increase in occurrence. Although medical science has long desired a prophylaxis of atopy and an enhancement of the quality of life, the recent increase in frequency has now exacerbated this need.
By the 1920s, it was recognized that early childhood nutrition plays an important role in preventive medicine. R. S. Zeiger et al., in "Journal of Allergy and Clinical Immunology", 78 (1 Part 2):224-238 (1986), stated that breast-feeding in combination with a delayed supply of solid nutrients is suitable to alleviate atopic dermatitis and food allergies in early childhood. Moreover, similar results were obtained by U. M. Saarinen, et al. (in "The Lancet", Jul. 28, 1979, pp. 163-166), where the authors of this clinical study attempted to explain the effect of prolonged breast-feeding in terms immunoglobulin A (IgA) secreted in human milk blocking the action of antigens on the intestinal mucosa.
Efamol Limited has developed pharmaceutical and dietetic compositions containing linoleic acid metabolites (including dihomo-.gamma.-linolenic acid) for use in the treatment of manifest atopy. For example, Horrobin in U.S. Pat. No. 4,681,896, issued Jul. 21, 1987, teaches a method for treating atopic disorders. In this treatment, one or more metabolites of linoleic acid and one or more metabolites of .alpha.-linolenic acid are administered as such, or in the form of an ester, salt, amide or other derivative convertible in the body thereto alone or in an acceptable pharmaceutical carrier or diluent. (This patent is herein incorporated by reference.) As clearly evidenced in this patent, the role of desaturase enzymes, such as .DELTA.-6-desaturase, was thought to be the critical component in the treatment of atopic dermatitis.
It is recognized that a .DELTA.-6-desaturase deficiency or a deficient supply of linoleic acid metabolites is a cause for the subsequently occurring clinical manifestation of atopy, for reasons unrelated to the subject method of prophylaxis. In the case of .DELTA.-6-desaturase deficiency, linoleic acid cannot be normally metabolized.
The subject invention focuses on the appropriate maturation and early differentiation of atopic lymphocytes in the thymus, the primary organ of the immune system. This has nothing in common with the correction or manipulation of functional disturbances of already inappropriately differentiated atopic T cells during manifest atopic disease as described by Horrobin.
DE-A-34 03 251 relates to a pharmaceutical dietetic composition for use in the treatment of atopic disorders wherein effective amounts of one or more metabolite(s) of linoleic acid and one or more metabolites of the .alpha.-linolenic acid are contained. Upon administration of .gamma.-linolenic acid in the form of Evening Primrose Oil, biochemical deficits in manifest atopy are in part compensated for, and clinical improvements are provided.
From Chemical Abstracts, 98: 69 996v, it is known that .gamma.-linolenic acid in the form of Evening Primrose Oil (Efamol) is capable of partially correcting the biochemical anomalies and the clinical status in manifest atopic dermatitis.
Traitler, et al. in U.S. Pat. No. 4,703,060, issued Oct. 27, 1987, describe a nutritive composition containing fatty substances and a process for their preparation. However, no mention is made of the use of these compositions in treating, much less preventing atopy.
From Chemical Abstracts, 100: 80453w, it is known that the increased capillary permeability in skin by intravenous injection of chemical mediators such as histamine, serotonin and bradykinin, is suppressed by the subcutaneous injection of prostaglandin E.sub.1 (PGE.sub.1). Investigations carried out with rats demonstrated an in vivo effect of prostaglandins on the capillary permeability in immediate type allergic reactions.
Chemical Abstracts, 109: 209935x, relates to a food composition containing omega(.omega.)-6-unsaturated fatty acids which are alleged to serve in the prevention and treatment of atopic dermatitis, in addition to other purposes. More particularly, a jelly containing only 3% .gamma.-linolenic acid oil (corresponding to 8% of .gamma.-linolenic acid in the oil) is stated as preventing "hangover". The prevention of atopic dermatitis, however, is the treatment of persons already suffering from manifest atopic disease as described by Horrobin.
EP-A-0 292 403 relates to prostaglandin-lipid formulations which may be used for the treatment of, among other things, bronchial asthma.
Because of ethical considerations, appropriate maturation and early differentiation of atopic lymphocytes in the human thymus could not be evaluated. However, since filing the parent patent application, the subject method of preventing atopy has received widespread approval of leaders in the fields of dermatology and medicine. Moreover, a recent paper (B. Dvorak and R. Stepankova, "Prostaglandins Leukotrienes and Essential Fatty Acids", 40:183-190 (1992), herein incorporated by reference) has reported that "the period immediately following birth, characterized by rapid development of neuroendocrine regulation in very young rats, crucially affects not only the physiological development of the organism but also development of the immune system. A nutritional deficiency of essential fatty acids in this period inflicts serious damage on the function of thymus, imposing a long-term effect on the cell-mediated immune response." Thus, in vivo support now exists for the subject method.
No method for atopy prophylaxis and prevention has ever previously been described.
Known treatments of atopy have generally used substances such as antihistamines, glucocorticoids and beta-sympatheticomimetic agents. In practice there has long been a great need for fast-acting substances which, especially in the case of an acute manifest atopy in the dermal and mucosal regions, will provide immediate relief.
The subject invention further provides a new use for PGE.sub.1, PGE.sub.1 derivatives and PGE.sub.1 analogs, their physiologically compatible salts, esters, amides, phospholipids and glycolipids thereof as well as their precursors for the topical and inhalative treatments of acute manifest atopies in the dermal and mucosal areas.
Japanese Laid-Open Patent Application [JP-OS] 88/145230 (63/145230) relates to the use of prostaglandin E.sub.1 as a therapeutic and prophylactic pharmaceutical for the treatment of certain brain diseases. It is also known from the JP-OS 87/223120 (62/223120) that AIDS may possibly be controlled by a combination treatment with various prostaglandins.
According to the EP-OS 257 859, a combination tissue plasminogen activator-prostaglandin can be used as a thrombolytic agent. EP-OS 100 630 relates to analogs of PGE.sub.1 which can be employed for protection against cytotoxic substances, above all in the liver. From the German Laid-Open Patent Application DE-OS 33 15 356 it is known that PGE.sub.1 derivatives and their cyclodextrin inclusion complexes as well as their salts can be employed, when administered orally or parenterally, against brain ischemia. Various other literature references relate to the synthesis and use of PGE.sub.1 derivatives and analogs.
No above-mentioned reference anticipates, teaches or suggests the use of prostaglandin E.sub.1, its derivatives, analogs and precursors for the treatment of forms of acute manifest atopy in the dermal and mucosal areas.